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COMMON GCP INSPECTION FINDINGS2018
Sumitra SachidanandanRegulatory Consultant
Innovation Office & Clinical Trials BranchHealth Products Regulation Group
Health Sciences Authority Singapore
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OUTLINE
• General Overview
• GCP Inspections
• MS IIT Inspections
• Sponsor Inspections
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HSA Inspections over the past 9 yrs 126
0
2
4
6
8
10
12
14
16
18
20
2009-2010 2011 2012 2013 2014 2015 2016 2017 2018
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Types of Inspections in 2018 (N=19)
NEW!
0 2 4 6 8 10 12 14 16 18
GCP (Site)
MS IIT
Sponsor
3
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Distribution by Therapeutic Area (N=19)
0
5
10
15
20
25%
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Distribution by Phase of Clinical Trials(N=19)
I10%
II37%
III37%
IV16%
I II III IV
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Distribution by Sponsor (N=19)
0
10
20
30
40
50
60
70
Industry Institution
%
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OUTLINE
• General Overview
• GCP Inspections
• MS IIT Inspections
• Sponsor Inspections
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Objectives of GCP Inspections
► To safeguard the Rights, Safety and Well-Being of trial subjects.
► To verify the Quality and Integrity of the clinical trial data submitted to the Regulatory Authority.
► To assess Compliance to protocol and applicable regulations, guidelines and standard operating procedures for clinical trials.
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Classification of GCP Inspection Findings
• Critical: Conditions, practices or processes that adversely affect the rights, safety or well being of the subjects and/or the quality and integrity of data.
• Major: Conditions, practices or processes that might adversely affect the rights, safety or well-being of the subjects and/or the quality and integrity of data.
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Classification of GCP Inspection Findings
• Other: Conditions, practices or processes that would not be expected to adversely affect the rights, safety or well being of the subjects and/or the quality and integrity of data.
• Comments: The observations might lead to suggestions on how to improve quality or reduce the potential for a deviation to occur in the future.
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Classification of GCP Inspection Findings
0 10 20 30 40 50 60 70 80 90 100
2018 (N=38)
2017 (N=27)
2016 (N=27)
2015 (N=29)
2014 (N=22)
2013 (N=24)
2012 (N=26)
2011 (N=62)
2009-2010 (N=95)
OTHER MAJOR CRITICAL
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Distribution of GCP Inspection Findings in 2018 (N=17)
0
5
10
15
20
25
30
% Major %OtherIRB = Institutional Review BoardRA = Regulatory SubmissionsISF = Investigator Site FileIP = Investigational ProductSD & CRF = Source Document & Case Report Form
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GCP Inspection Findings in 2018INVESTIGATIONAL PRODUCT (IP)
IP administration on site
IP administration at home
Electronic Patient Reported Outcome (ePRO)
device
IP Dispensing & Accountability
Logs
• Discrepancies concerning ePRO data for IP administration:
► Missing entries in ePRO device
► Lack of traceability between ePRO data, IP docs and eCRF
► Lack of review of ePRO data by study staff Ref.: Section 4.9.0 of ICH E6 (R2) GCP Guidelines
Electronic Case Report Form
(eCRF)
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Electronic Patient Reported Outcome (ePRO) devices
Data entry
Data review
Data query
Data clarification
Subjects should be trained to enter data in ePRO device.
Site staff should review the ePRO data periodically.
Data changes should be supported by adequate source documentation.
Data changes should be authorised by the site staff.
CONTROL & ACCESS BY
INVESTIGATOR &
SPONSOR
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GCP Inspection Findings in 2018INVESTIGATIONAL PRODUCT (IP)
• Inadequate quality control in the management of the IP expiration date, resulting in ambiguity in the assignment of the initial expiry date and labelling error.
Ref.: Section 2.13 of ICH E6 (R2) GCP Guidelines
Date of manufacture
(e.g. Jan 2018)
Date of initiation of
stability study(e.g. Feb 2018)
InitialIP expiry date(e.g. 3 mths)
Manufacturer determined initial expiry date is Apr 2018.
Sponsor determined initial expiry date is May 2018.
IP LabelExpiry:
May 2018
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Determination of IP expiry date
CoA IP Label IP Documentation
CoA : Certificate of Analysis
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GCP Inspection Findings in 2018INVESTIGATIONAL PRODUCT (IP)
• Discrepancies in IP labelling:
► Reasons for Labelling Omissions Form had not been submitted to request for waiver of Subject ID on IP label.
► IP expiry date had not been updated on the primary packaging. It had only been updated on the secondary packaging.
► Vial ID had been used as the Subject ID, as Study Pharmacist was unaware of the actual Subject ID.
Ref.: Paragraph 1(2) of the Second Schedule of the Health Products (Clinical Trials) Regulations
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►Check if the IP label is compliant with applicable clinical trials and clinical research materials regulations.
►Refer to HSA Guidance on Labelling of TP and MP Used in Clinical Trials for further guidance.
►Submit a Reasons for Labelling Omissions Form to request for a waiver, if applicable.
►Subject ID should be communicated to the Study Pharmacist.
► IP relabelling applies to all types of IP packaging.
IP Labelling
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GCP Inspection Findings in 2018CASE REVIEW
• Lack of adequate source documentation.
Ref.: Section 4.9.0 of ICH E6 (R2) GCP guidelines
• Source documents were not attributable.
Ref.: Section 4.9.0 of ICH E6 (R2) GCP guidelines
• Eligibility criteria in Eligibility Checklist did not co-relate with study protocol.
Ref.: Study protocol
• Study discontinuation procedures were not included in study protocol.
Ref.: Study protocol
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►Accurate
► Legible
►Contemporaneous
►Original
►Attributable
ALCOA principles
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GCP Inspection Findings in 2018REGULATORY SUBMISSIONS
• Trial Status Reports were not submitted to HSA.
Ref.: Regulation 12(1) of the Health Products (Clinical Trials) Regulations
• Substantial amendments to the protocol / ICF had not been submitted to HSA.
Ref.: Regulation 10(2) of the Health Products (Clinical Trials) Regulations
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►Refer to the HSA Guidances:
■ Regulatory requirements for new applications and subsequent submissions to HSA.
■Determining whether an amendment to a clinical trial is a substantial amendment.
►Consult HSA when in doubt.
►Be familiar with the timelines for regulatory submissions to HSA.
Regulatory Submissions to HSA
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Regulatory Submissions to HSA
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GCP Inspection Findings in 2018STUDY STAFF
• Study staff had performed IP administration without being delegated by the PI. CVs and training records had also not been maintained.
Ref.: Section 4.1.5, 4.2.4, 8.3.24 of ICH E6 (R2) GCP guidelines
• Study staff had received IP prior to delegation by PI.
Ref.: Section 4.6.2 of ICH E6 (R2) GCP guidelines
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► Prior to conducting any study procedures, study staff should be:■ Adequately qualified
■ Trained on study protocol, CITI, GCP (mandatory for PI)
■ Delegated by PI on Signature Sheet
► Maintain a Study Staff Tracking Log to track:■ Start date and end date
■ IRB approval (for investigators)
■ CV
■ Medical Licence (for investigators)
■ Financial Disclosure Forms
■ CITI
■ GCP (mandatory for PI)
■ Study-specific training
Study Staff
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Study Staff
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OUTLINE
• General Overview
• GCP Inspections
• MS IIT Inspections
• Sponsor Inspections
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MS IIT Inspection Findings 2018INVESTIGATIONAL PRODUCT (IP)
• IP receipt
► Inadequate documentation of IP receipt and inventory.
Ref.: Section 4.6.3 of ICH E6 (R2) GCP guidelines)
• IP repackaging and relabelling
► No documentation of IP repackaging and relabelling process.
► No witness to verify the repackaging process.
Ref.: Section 5.14.3 of ICH E6 (R2) GCP guidelines)
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MS IIT Inspection Findings 2018INVESTIGATIONAL PRODUCT (IP)
• IP Preparation
► Blinded investigators had signed off on the IP Preparation Form that had been completed by the unblinded study team, thereby potentially compromising the study blind.
Ref.: IP Management SOP
• IP Administration
► Baseline weight for calculation of IP dose could not be traced to source documents.
Ref.: Section 4.9.2 of ICH E6 (R2) GCP Guidelines
► Nurses had not been trained on IP administration.
Ref.: Section 4.2.4 of ICH E6 (R2) GCP Guidelines
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MS IIT Inspection Findings 2018INVESTIGATIONAL PRODUCT (IP)
• Blinding
► File note regarding treatment assignment for a subject had been signed off by the blinded PI.
► Blinded investigator had been given access to the randomisation system.
Ref.: Section 4.2.4 of ICH E6 (R2) GCP Guidelines
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IP Management for MS IIT studies
• Develop an IP Management SOP for the clinical trial.
• Same IP Documentation templates should be used across all trial sites.
• Site staff involved in IP management from various trial sites should be in regular contact.
• Consider cross-institution monitoring of IP management for quality control purposes.
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OUTLINE
• General Overview
• GCP Inspections
• MS IIT Inspections
• Sponsor Inspections
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SPONSOR INSPECTION
• Scope
► Quality Assurance and Quality Control
► Outsourced services
► Investigator Selection
► Investigational Product management
► Safety Reporting
► Monitoring
► Data Collection and Handling
► Essential Document management
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Sponsor Inspection
• Objectives
1. To evaluate the quality assurance and quality control systems established by the sponsor / CRO in order to assure that clinical trials are conducted and data are generated, recorded and reported in compliance with the protocol, applicable regulations, guidelines and standard operating procedures for clinical trials.
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Sponsor Inspection
• Inspection Criteria
• Inspectee
► Local Sponsor
(i) Protocol(ii) Applicable clinical trials and clinical research materials regulations*(iii) ICH E6 (R2) Good Clinical Practice Guidelines [ICH E6 (R2) GCP](iv) Applicable Sponsor / Contract Research Organization (CRO) / Site
Standard Operating Procedures for clinical trials
* Health Products (Clinical Trials) Regulations, Medicines (Clinical Trials) Regulations, Health Products (Therapeutic Products as Clinical Research Materials) Regulations, Medicines (Medicinal Products as Clinical Research Materials) Regulations, Health Products (Medical Devices) Regulations
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Sponsor Inspection Process
Preparation
• Notice of Sponsor Inspection sent to local sponsor within 30 working days of sponsor inspection.
• Sponsor should complete and send the Sponsor Inspection Dossier to HSA within the stipulated timeline.
Conduct
• Sponsor inspection will be conducted at local trial site(s), CRO (if applicable) and local sponsor office.
• Access to IWRS, electronic Trial Master Files (eTMF), electronic Case Report Forms (eCRFs) required before sponsor inspection.
Follow-up
• Sponsor Inspection Report will be sent to local sponsor within 20 working days of Sponsor Inspection.
• Sponsor should complete and submit the Corrective Action and Preventive Action (CAPA) Plan to HSA within 30 working days.
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Grading of Sponsor Inspection Findings
• Similar to grading of GCP Inspection Findings.
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Conclusions
• Be familiar with the study protocol, regulations, GCP and SOPs.
• Quality systems should be implemented in every aspect of the clinical trial.
• Risk-based approach should be adopted in quality systems.
• Think outside the box.
• Rules of thumb:
► If it was never documented, it was never done.
► It is always better to prepare than repair.
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THANK YOU!
We welcome your enquiries and feedback!
